Properdin deficiency associated with recurrent otitis media and pneumonia, and identification of male carrier with Klinefelter syndrome
Introduction
Properdin is a basic glycoprotein, synthesized by peripheral blood T-cells, monocytes and neutrophils [1], [2], [3], and normally present in serum at concentrations between 11–37 mg/l [4].
Patients with properdin deficiency have a 250-fold higher risk of meningococcal disease than the general population [5]. The mean age at onset of symptoms is 12–14 years and the mortality rate from meningococcal disease is high (33–50%), but recurrent disease is uncommon in contrast to patients with late complement component deficiencies [5], [6], [7]. Within a family, properdin deficient relatives have 18% risk of meningococcal disease, and the susceptibility to disease may be promoted by other factors in the immune system such as MBL-deficiency or lack of the IgG2 allotype marker G2m(n) [4], [5], [8].
Properdin is essential for efficient activation of complement via the alternative activation pathway (AP): In the standard version of AP activation C3 is spontaneously cleaved to C3a and C3b. C3a functions as a chemo attractant while unspecific binding of C3b to foreign surfaces facilitates the binding of factor B. Cleavage of factor B and release of Ba generates the AP C3 convertase complex C3bBb, which accentuates C3 cleavage and activation of the downstream complement cascade. Binding of properdin to C3bBb is essential for efficient AP activation; it stabilizes the otherwise labile complex, extending the half-life up to 10-fold [9]. Moreover, recent studies have suggested a more active role of properdin as an initiator of the AP pathway and are central for the conceptual understanding of properdin deficiency in relation to disease [10], [11], [12]: properdin binds to bacterial surfaces – probably as an innate pattern recognition molecule – and promotes C3b-deposition and formation of the C3bBbP-complex. Indeed, bacterial surfaces that bind properdin activate AP rapidly while bacterial surfaces that do not bind properdin activate AP slowly [12]. The surface of Neisseria strains contains lipooligosaccharide (LOS). C3b only binds to the surface of Neisseria gonorrhoeae if it is pre-treated with properdin [12], and it has been shown that LOS-induced systemic complement activation does not occur in serum from properdin deficient mice, suggesting that complement activation through the alternative pathway is essential for complement activation in response to Neisseria[11].
The first description of properdin deficiency was in patients from Sweden in 1982 [13]. Since then, genetic analyses have shown a great heterogeneity among 24 families with identification of 16 different mutations in the Properdin gene (PFC) [14], [15]. The inheritance of properdin deficiency is X-linked recessive: PFC is located on Xp11.3–Xp23 and consists of 10 exons covering approximately 6 kb [16], [17], [18]. The monomeric properdin molecule consists of six repetitive Type-I repeat sequence (TSR)-like domains surrounded by the N- and C-terminal regions [19]. The monomers oligomerize in head to tail orientation into di- tri- and tetrameric molecules which are present in serum in an approximate ratio of 1:2:1 [20], [21]. Properdin deficiency has been divided into three categories; tpI with no (< 0.01 mg/l) properdin in serum, tpII with < 10% properdin in serum, and tpIII with normal concentration but dysfunctional properdin in serum. TpI properdin deficiency is caused by nonsense or missense mutations that may interfere with oligomerization of properdin in di- tri- and tetramers. mRNA transcription is normal in cells of tpI deficient patients but no protein is detected probably due to rapid intracellular degradation [22]. All nonsense mutations described so far result in truncated proteins that lack TSR6 which has been shown to be necessary for oligomerization [23]. In tpII deficiency, properdin is synthesized and secreted from the cells, but oligomerize in an abnormal pattern with a dominance of dimers. The reduced properdin concentration in tpII deficiency is probably due to rapid extracellular degeneration of abnormal properdin molecules [22]. Only one case of properdin deficiency tpIII has been described as yet. This was caused by a missense mutation, which affected the binding of properdin to C3b [24].
Most of the properdin deficient patients described so far have been Caucasian of origin, either due to an overrepresentation of properdin deficiency among Caucasians or due to insufficient research of properdin deficiencies in other populations [14].
Here we describe the genetic background of properdin deficiency in a family of Pakistani origin. The genetic analyses identified four properdin deficient patients including a son of an unexpected female carrier, and surprisingly a male carrier with Klinefelter syndrome was found. Prior to the genetic analysis a structured interview regarding previous infections was performed. This revealed an association between properdin deficiency and recurrent otitis media, as well as pneumonia.
Section snippets
Patients
Twenty-four members from three generations of a Pakistani family were included in the study after informed consent. The grandparents in the family (I:1,1:2) are ancestors of an Indian family, who fled to Pakistan during the conflict between Kashmir and Punjab. In 1973 they (I:1,1:2) immigrated to Denmark with their oldest children. Their youngest daughter (II:2) and their grandchildren were born in Denmark.
Analysis of the complement system
Screening of the classical, alternative and lectin complement pathways was performed
Case studies
Case 1 + 2: The index patients (III:1 + 2) were two identical twins with consanguineous parents of Pakistani origin. They were born at the gestational age of 33 weeks by elective caesarean section due to intrauterine growth retardation in twin A. Patient III:1. Twin A, birth weight 1600 g, was treated within the first week for suspected septicemia. Blood cultures for bacterial pathogens were negative, and the recovery was uneventful. From the age of 15–16 months, he had been ill every other month with
Discussion
Properdin deficient patients have previously been identified mostly by immunological evaluation of patients after meningococcal disease or in studies of relatives of these patients [7], [13], [26], [28], [29], [30], [31], [32], [33]. In the present study properdin deficiency was identified in patients who underwent immunological evaluation because of recurrent non-meningococcal infections. Recurrent infections have not previously been significantly linked to properdin deficiency, even though
Acknowledgments
Excellent technical assistance was performed by Ewa Szöjmer. This work was supported by grants from the Novo-Nordisk Research Foundation, Birthe and John Meyer Foundation, Rigshospitalet and the Danish Medical Research Council.
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The role of properdin and Factor H in disease
2022, Advances in ImmunologyCitation Excerpt :Although deficiency of properdin leads to severe fulminant meningococcal infections, preventive vaccination to increase opsonization mediated by antibodies and C3b are important for the general population for properdin-deficient and MAC-deficient individuals (Barnum, 2017). In a retrospective study of a Pakistani family, Schejbel, et al. established a new association between properdin deficiency and recurrent otitis media and pneumonia (Schejbel, Rosenfeldt, Marquart, Valerius, & Garred, 2009). Reports of repeated episodes of otitis media and pneumonia were documented more frequently among the 4 properdin-deficient males compared to their relatives (Schejbel et al., 2009), though a prospective study is warranted to confirm this association.
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